tbuckley/cabot-search huggingface dataset:
Effect of more versus less frequent abdominopelvic computed tomography follow-up testing on overall survival in patients with stage II or III colon cancer.
Authors: Jeon Jeongseok, Da Bin Lee, Seung-Hoon Beom, Sang Joon Shin, Joong Bae Ahn, Han Sang Kim
Journal: Journal of Clinical Oncology (2022)

3604 Background: Patients with colon cancer undergo an abdominopelvic computed tomography (AP-CT) scan surveillance every 6-12 months for five years after surgery. However, evidence of survival benefit from more intensive AP-CT patients in stage II and III colon cancer is still elusive. Methods: A total of 2,137 patients with stage II-III colon cancer who received curative aim surgery were analyzed in the Yonsei Cancer Registry Database between Jan 1, 2005, to Dec 31, 2015. The surveillance start date was defined as 90 days after curative resection or one day after adjuvant chemotherapy. All patients had at least one AP-CT for two years after the surveillance period. The average interval of AP-CT per patient was calculated as the postoperative surveillance duration divided by the number of AP-CT examinations. Patients who underwent AP-CT with an average interval of 6 months and 12 months were assigned to the high-frequent and low-frequent surveillance groups. Association of AP-CT frequency and demographic factors with overall survival (OS) were evaluated. Univariate and multivariate analyses were conducted. Results: Among 2,137 patients who underwent curative aim surgery, the median intervals of AP-CT scan were 6.1 months in high-frequent surveillance and 10.8 months in the less-frequent surveillance group, respectively. The 5-year overall survival (OS) was not significantly different in both groups; however, OS was significantly longer in the high-frequent surveillance group of patients who harvested lymph nodes less than 12 in curative resection ( P = 0.015) or measured postoperative serum carcinoembryonic antigen (CEA) level higher than 5 ng/ml ( P = 0.023). Of note, high-frequent surveillance group detected liver metastasis earlier (6.7 months) than the low-frequent group, leading to more curative aim metastasectomy (28.0% vs 4.3%, P = 0.020), and significantly longer 5-year OS (62.2% vs 34.8%, P = 0.017). Multivariate analysis showed that harvesting lymph nodes less than 12 (HR = 4.37, P = 0.004) and postoperative CEA level higher than 5 ng/ml (HR = 7.39, P &lt; 0.001) were prognostic factors for overall survival. Conclusions: The average interval of AP-CT in patients with stage II-III colon cancer is not associated with improved OS. However, a high-frequent AP-CT enabled early detection of liver metastases, leading to the improved OS in high-risk patients, including the number of harvested lymph nodes less than 12 or postoperative CEA level is higher than 5 ng/ml. The risk-stratified approach is warranted to guide postoperative colon cancer surveillance.
Study to evaluate intraperitoneal (IP) ONCOS-102 with systemic durvalumab in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Phase 2 results.
Authors: Dmitriy Zamarin, Kunle Odunsi, Emese Zsiros, Brian M. Slomovitz, Agustin Pimentel, Linda R. Duska, Matthew Reilley, John J. Nemunaitis, Danae M. Hamouda, Hitendra Patel, Neil Howard Segal, Giulio Pesci, Aliya Holland, Lisa Shohara, Paul Otto Schwarzenberger, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Magnus Erik Jaderberg, Ralph Rudolph Venhaus
Journal: Journal of Clinical Oncology (2022)

2600 Background: Locoregional treatment with oncolytic viruses may be used to improve the efficacy of immune checkpoint inhibitors at both treated and distant tumor sites. This study evaluated the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GM-CSF), with systemic durvalumab (durva) in patients (pts) with advanced OC or CRC who have failed prior chemotherapy. Methods: This open-label study (NCT02963831) evaluated ONCOS-102 (IP 3 x 10 11 VP in 500ml saline [recommended phase 2 dose] weekly x 6) + durva (IV 1500 mg every 4 weeks x 12). One dose of cyclophosphamide was given prior to first ONCOS-102 dose. Phase 2 evaluated the activity of the combination using Simon’s 2-stage MINIMAX design. In MINIMAX stage 1, if ≥ 5 of 18 OC pts or ≥ 1 of 13 CRC pts met the efficacy criteria (progression free at end of week 24), 15 additional OC pts or 14 additional CRC pts were to be enrolled in stage 2. The efficacy endpoint would be met if ≥ 11 OC pts or ≥ 4 CRC pts remained progression free at 24 weeks. Safety, response rate and progression-free survival (PFS) by RECIST 1.1, overall survival (OS), and immunologic effects in tumors were evaluated. ITT population = all pts who received at least one dose of durva or ONCOS-102; per protocol (PP) population = all pts who received at least 60% of ONCOS-102 doses and at least 1 durva dose in the first 2 cycles. Results: In MINIMAX stage 1, the OC cohort did not meet the efficacy criteria and was closed. For CRC, stage 1 efficacy criteria were achieved and the cohort was opened for stage 2. As of the 14 Dec 2021 cutoff, CRC enrollment was complete, and all pts were followed for 24 weeks or until progression or off study. Two pts were progression free at 24 weeks (see table). Treatment-related adverse events (TRAEs) occurring in &gt; 30% pts were vomiting, nausea, fatigue, chills, and pyrexia. There were no grade 4 or 5 TRAEs. Grade 3 TRAEs were reported in 8 pts, 2 in the OC cohort and 6 in CRC. All grade 3 TRAEs occurred in no more than 1 pt for each AE except abdominal pain, which occurred in 2 pts. Conclusions: The combination of IP ONCOS-102 and durva was well tolerated. The study did not meet its efficacy endpoint. Evaluation of pre- and on-therapy translational parameters is ongoing. Clinical trial information: NCT02963831. [Table: see text]
<i>DYNC2H1 </i>Mutation as an indicator stratified patients benefit from Immune Checkpoint Inhibitors in NSCLC.
Authors: Chunxiang Li, Lele Zhao, Yangyang Yu, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e21052 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) encodes a large cytoplasmic dynein protein that involved in intraflagellar transport. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between DYNC2H1 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between DYNC2H1 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with DYNC2H1 mutation were significantly associated with better PFS (HR = 0.3; 95% CI, 0.14-0.64; P= 0.001), objective response rate (ORR, 65.0% vs 27.6%; P = 0.003) and durable clinical benefit (DCB, 75.0% vs 43.4%; P = 0.031) after ICIs therapy, compared with those with wide-type DYNC2H1. DYNC2H1 mutation were associated with increased TMB ( P &lt; 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between DYNC2H1 mutation and PFS remained significant (HR = 0.32; 95% CI, 0.14-0.73; P = 0.007). In contrast, no association between DYNC2H1 mutation and OS (LUAD: P = 0.97 ; LUSC: P = 0.34) or PFS (LUAD: P = 0.54; LUSC: P = 0.39) was observed in TCGA datasets, suggesting that DYNC2H1 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, DYNC2H1 mutation was significantly associated with higher CD8+ T cell. Moreover, DYNC2H1 mutation was associated with increased TMB ( P &lt; 0.001) and neoantigen load ( P &lt; 0.001) in TCGA. Conclusions: Our results demonstrated that DYNC2H1 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of DYNC2H1 in immunotherapy is needed to be further studied.
Targeting adiposity and inflammation with movement to improve prognosis in breast cancer survivors (the AIM trial): Rationale, design, and methods.
Authors: Christina Marie Dieli-Conwright, Dong-Woo Kang, Rebekah M Wilson, Paola Gonzalo-Encabo, Mary Norris, Marybeth Hans, Meghan Tahbaz, Jackie Dawson, Danny Nguyen, Amber Normann, Alexandra G Yunker, Nathalie Sami, Hajime Uno, Jennifer A. Ligibel, Steven D Mittelman
Journal: Journal of Clinical Oncology (2022)

TPS12140 Background: Obesity is considered a leading modifiable contributor to breast cancer mortality worldwide due to its association with increased recurrence and decreased overall survival rate. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise has shown potential in improving inflammation but has not been implemented with breast cancer survivors. Our hypothesis is that exercise designed to target chronic inflammation and associated sarcopenic obesity will improve prognosis in obese breast cancer survivors. Methods: The AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program compared to a traditional aerobic and resistance exercise (TARE) program, and attention control (AC) group, on adipose tissue inflammation in 300 breast cancer survivors. Main inclusion criteria are histologically confirmed breast cancer stage 0-III, completion of chemotherapy and/or radiation, sedentary, centrally obese, and free from musculoskeletal disorders. The primary endpoint is adipose tissue inflammation as assessed by core biopsy and blood draw; secondary endpoint is sarcopenic obesity; and exploratory endpoints are physical fitness and function and patient reported outcomes. Participants randomized to the exercise groups participate in three weekly supervised exercise sessions for 16-weeks. Participants randomized to the attention control group are offered the CARE intervention after the 16-week period of observation. Discussion: This is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Results will contribute to a better understanding of exercise modality on adipose tissue inflammation that can potentially improve patient prognosis. Clinical trial information: NCT03091842.
Safety and efficacy of YBL-006, an anti-PD-1 monoclonal antibody in advanced solid tumors: A phase I study.
Authors: Do-Youn Oh, John J. Park, Keun Wook Lee, Seung Tae Kim, Virote Sriuranpong, Sun Young Rha, Changhoon Yoo, Bhumsuk Keam, Dhanusha Sabanathan, Se Hyun Kim, Joon Oh Park, Napa Parinyanitikul, Min Hwan Kim, Kyu-Pyo Kim, Myungsuk Kim, Jaebong Yoon, Han Seung Lee, Chan-Young Ock
Journal: Journal of Clinical Oncology (2022)

e14557 Background: YBL-006 is a fully human anti-programmed death-1 (PD-1) antibody under evaluating its safety and efficacy in phase I clinical trial. We have reported interim analysis of dose escalation cohort which showed a tolerable safety profile. Here, we present the updated clinical activity of YBL-006 in dose escalation and expansion cohorts. Methods: Dose escalation (0.5, 2, 5, 10 mg/kg) and dose expansion (flat doses of 200 mg every 2 weeks [Q2W] and 300 mg every 3 weeks [Q3W]) cohorts explored the safety, pharmacokinetics (PK) and objective response rate (ORR) in the patients with advanced solid tumors who failed or were ineligible to the standard of care. Adverse events (AEs) were graded using the CTCAE v5. ORR was assessed using the RECIST (v1.1). Lunit SCOPE IO, an H&amp;E analysis tool, was applied as an exploratory biomarker, and samples with “Immune inflamed phenotype” were defined as those with high intratumoral TIL density in ≥ 20% of the tumor microenvironment. The cut-off date for analysis was Jan 4 th , 2022. Results: A total of 67 patients (safety set) with advanced solid tumors were enrolled in the study. Median follow-up duration of the safety set was 1.6 months (range 0.2-16.8). There was no dose-limiting toxicity during dose escalation phase. Most frequent AEs were grade 1 or 2; fatigue (19.4%), pruritus (10.4%), and fever (7.5%), and two hypothyroidism (3.0%), one pneumonitis (1.5%), and one cytokine-releasing syndrome (1.5%) were observed. One subject experienced grade 3 diarrhea in the safety set. PK study showed that half-life was 8.0 days, and mean C max and AUC 0-inf were 4.15 x 10 4 ng/ml and 1.12 x 10 7 ng/ml*h for 200 mg dose, and 6.26 x 10 4 ng/ml and 1.53 x 10 7 ng/ml*h for 300 mg dose, respectively. A total of 52 patients were evaluable for efficacy. ORR was 15.4%, including 1 complete response (penile squamous cell carcinoma [SqCC]), and 7 partial responses (two gastric adenocarcinomas, anal SqCC, paranasal sinus SqCC, nasopharyngeal carcinoma, neuroendocrine carcinoma, and thyroid Hurthle cell carcinoma). Durable responses were seen in 2 patients for over 12 months. Median duration of response was 4.9 weeks (range 1-65). Among efficacy set, 32 samples were available for Lunit SCOPE IO. ORR was significantly higher in inflamed immune phenotype compared to non-inflamed samples (62.5% vs 8.3% p = 0.005). Conclusions: Interim analysis of phase I trial of YBL-006 shows a tolerable safety profile and clinical activity. Notable anti-tumor efficacy was observed in inflamed immune phenotype. Clinical trial information: NCT04450901.
TLD-1, a novel liposomal doxorubicin, in patients (pts) with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).
Authors: Dagmar Hess, Ilaria Colombo, Simon Haefliger, Manuela Rabaglio, Sara Bastian, Michael Schwitter, Katrin Eckhardt, Jesus Glaus Garzon, Stefanie Hayoz, Christoph Kopp, Lisa Holer, Anna Mc Laughlin, Charlotte Kloft, Cristiana Sessa, Anastasios Stathis, Stefan Halbherr, Christian Baumgartner, Markus Joerger
Journal: Journal of Clinical Oncology (2022)

3027 Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional liposomal formulations of doxorubicin in preclinical in vivo mouse breast cancer models. This phase I first-in-human trial is aiming to determine the recommended phase II dose (RP2D), toxicity profile, pharmacokinetics and preliminary activity. Methods: Patients with a maximum of 3 prior lines of systemic chemotherapy and preferably anthracycline-sensitive disease were eligible. TLD-1 was administered on day 1 iv over 60-90 minutes (depending on individual dose) q 21 days, for up to 6 or 9 cycles (according to prior anthracycline-exposure) with premedication of 8mg dexamethasone. Dose escalation with dose levels (DL) 1-7 of 10, 16, 23, 30, 35, 40 and 45mg/m 2 started with an accelerated titration design, treating one pt at each DL up to DL6 (40mg/m 2 ) followed by a modified continual reassessment method at DL7 due to observed toxicity. Results: 30 pts (F:M = 24:6) have been treated, one each at DLs 1-6, 15 pts at DL7 and an additional 9 pts at DL6. Most frequent tumor types included breast (n = 13), ovarian (n = 6), cervical cancer (n = 2) and cholangiocarcinoma (n = 2). Median age was 67.5 years (range:38-83), 13 pts were exposed to prior anthracyclines. The median number of cycles was 4 (range:1-9). No dose-limiting toxicities (DLT) occurred during cycle 1. At DLs 1 to 5, no treatment-related G3 AEs (TRAE) were observed. At DL6, there was one case of mucositis G3, one of palmar-plantar-erythrodysesthesia (PPE) G3 and one of anemia and neutropenia G3 each. One patient with pre-existing valvular cardiopathy developed symptoms of heart-failure G3 after 8 cycles. Echocardiography showed severe mitral regurgitation with normal LV-EF. In addition one case of urinary-tract infection G3 was seen. Dose-modifications or -delays due to AEs occurred in 7/50 cycles. At DL7, one case of mucositis G3, 3 events of PPE G3 and one case of fatigue G3 were reported. In addition, one case of infection with shingles occurred. Dose-modifications or -delays due to AEs occurred in 12/61 cycles. Shingles and heart failure were reported as SAEs. All toxicities listed above were categorized as TRAE. 29/30 pts were evaluable for response. Three breast cancer pts had a partial response, 2 at DL7 and 1 at DL6, 14 pts had stable disease. Conclusions: No DLT was observed up to DL7. RP2D was defined at 40mg/m 2 due to cumulative PPE G3 at DL7. The trial is ongoing with a comparative PK-part evaluating the two iv liposomal formulations of doxorubicin TLD-1 and Caelyx. Clinical trial information: NCT03387917.
Multi-omics characterization of productive HPV integration in cervical cancer.
Authors: Chaoyang Sun, Junpeng Fan, Yu Fu, Wenju Peng, Xiong Li, Yuanming Shen, Dongling Zou, Bairong Xia, Kun Song, Gang Chen, Ding Ma
Journal: Journal of Clinical Oncology (2022)

e17508 Background: Cervical cancer (CC), which is caused by high-risk human papillomavirus (HPV), remains a significant public health problem worldwide. HPV integration into the host genome is a critical aetiological event in cervical carcinogenesis and progression and it can be silent or actively transcribed that leads to production of viral-host fusion transcripts. We aim to study the characterization of silent and productive HPV integration in cervical cancer. Methods: Cervical cancer (CC), which is caused by high-risk human papillomavirus (HPV), remains a significant public health problem worldwide. HPV integration into the host genome is a critical aetiological event in cervical carcinogenesis and progression and it can be silent or actively transcribed that leads to production of viral-host fusion transcripts. We aim to study the characterization of silent and productive HPV integration in cervical cancer. Results: Virus capture sequencing revealed 762 virus-host DNA fusion breakpoints and only 142 (18.6%) were actively transcribed into fusion transcripts. The productive HPV integrations were nonrandom, with an increase in breakpoints in the HPV E1 region、 human introns and common fragile sites. They were associated with significant changes in host focal genome structure and gene transcription, but not in protein production in 40 kb region, and produced higher levels of E6 and E7 proteins detected by Western Blot. Clinical, transcriptional, proteomic, phosphoproteomic and single-cell data demonstrated that EMT, proliferation and extracellular matrix associated pathway were enriched in productive HPV integrated tumors and contributed to advanced clinical stage. Conclusions: We demonstrated that productive HPV integration is associated with higher E6/E7 proteins and enhanced tumor aggressiveness and immunoevasion in situ to advanced disease. This study improves our understanding of the effects of HPV fusion transcripts on the biology and pathophysiology of HPV-driven cervical cancer that has the potential to direct new prevention and therapeutic strategies
Clinical outcomes following termination of immunotherapy due to long-term benefit in MSI-H colorectal cancer.
Authors: Kristen Simmons, Bryan K. Kee, Kanwal Pratap Singh Raghav, Benny Johnson, Scott Kopetz, Jason Willis, Arvind Dasari, Eduardo Vilar Sanchez, Kaysia Ludford, Christine Megerdichian Parseghian, Michael Sangmin Lee, Phat Le, John Paul Y.C. Shen, Michael J. Overman, Van K. Morris
Journal: Journal of Clinical Oncology (2022)

3585 Background: Immune checkpoint blockade therapy improves survival in patients (pts) with microsatellite instability-high (MSI-H) advanced colorectal cancer (CRC). Oncologists often discontinue immunotherapy after 2 years of disease control based on prior trial data. Recurrence outcomes following discontinuation of immunotherapy and clinicopathologic features associated with recurrence remain underreported given the recent advent of these agents for pts with MSI-H advanced CRC. Methods: Records from pts with MSI-H CRC from MD Anderson Cancer Center who received immunotherapy between 2015-2022 and stopped after clinical benefit were reviewed. Median survival was estimated according to the Kaplan-Meier method. Associations between the event of recurrence and coexisting mutations ( KRAS, NRAS, BRAF V600E , PIK3CA, APC, TP53, POLE/POLD), metastatic site (lung, liver, lymph nodes, or peritoneum), primary tumor sidedness (right vs. left colon), and prior immunotherapy (anti-PD-(L)1 alone or with anti-CTLA-4 antibodies) were measured by Fisher’s exact tests. Results: Thirty-six pts with MSI-H CRC without progression on immunotherapy were reviewed. Of these 29 and 7 received anti-PDL1 antibody alone or in combination with anti-CTLA-4 antibody, respectively. Median exposure to prior immunotherapy was 24 months (range, 5-43). After a median follow-up of 19 months (95% CI, 14-26) after stopping immunotherapy, 30 of 36 pts (83%) remained without disease progression. For the 6 patients with progression after stopping, median time to relapse was 13 months (range, 5-31). Median disease-free survival (DFS) was not reached. The estimated 1-year, 2-year, and 3-year DFS probabilities were 90% (95% CI, 79-100), 79.1% (95% CI, 64-98), and 68% (95% CI, 47-98), respectively. Median overall survival from the time that immunotherapy was stopped was 54 months (95% CI, 47-NA). Only 1 pt died due to unrelated illness. There were no observed associations between disease recurrence and co-existing mutations, metastatic organ involvement, primary tumor sidedness, or immunotherapy used. Conclusions: Most pts with MSI-H advanced CRC who achieve initial clinical benefit and do not progress on immunotherapy do not recur after treatment is stopped. Our data suggest that favorable outcomes do occur following cessation of immunotherapy in this setting even with concomitant prognostically unfavorable clinical features (RAS, BRAFV600E mutations; liver, peritoneal metastases).
An AI-based, automated workflow for identification and scoring of invasive tumors in Ki-67 stained breast cancer specimens.
Authors: Bhavika Patel, Stephanie Allen, Sameer S. Talwalkar, Navi Mehra, Jeppe Thagaard, Thomas W. Ramsing, Agnete Overgaard, Jeni Caldara
Journal: Journal of Clinical Oncology (2022)

e15108 Background: Understanding the rate of tumor cell growth in breast cancer specimens may be indicative of disease aggressiveness, a tumor characteristic which can be used to make an informed treatment decision. The nuclear protein Ki-67 is increased in cells as they prepare to divide or proliferate and is therefore widely used as a proliferation marker for tumor progression. This degree of tumor cell proliferation, or the proliferative index, is commonly detailed in pathology reports shared with the patient care team. Methods: In this study, we utilized the Ki-67 [K2] immunohistochemistry (IHC) assay to stain 10 breast cancer specimens. Stained slides were imaged using the AT2 scanner (Leica Biosystems, Buffalo Grove, IL) and analyzed using the Visiopharm Image Analysis platform. Results: Previous efforts to assess Ki-67 positivity utilizing image analysis have relied on the use of a secondary stain or manual effort by the pathologist to exclude non-invasive tumor regions. These antiquated methods are costly to the lab as they require additional materials or valuable pathologist time. Our novel image analysis approach utilizes artificial intelligence (AI) to automatically denote non-invasive verses invasive tumor regions, which can then be used to quantify the Ki-67 proliferative index. Conclusions: This valuable tool will allow for greater accuracy, cost-savings, and time efficiency when analyzing breast cancer samples compared to traditional methods.